Method of treating parkinsonism with morphanthridine derivatives



United States Patent U.S. Cl. 424244 4 Claims ABSTRACT OF THE DISCLOSURE The inventive method comprises administering a safe and effective amount of a selected morphanthridine derivative to an animal, especially a human being, afflicted with Parkinsons disease or a drug-induced extrapyramidal disorder to control the symptoms of the disease. Specific morphanthridine derivatives disclosed are S-methyl-l l-(3- piperidino)propyl-S,6-dihydromorphanthridine, S-benzyl- 11 [4-(N-methylpiperidylene]-S,6-dihydromorphanthridine and S-methyl-l 1-( 3-dimethylamino) propylidene-5,6- dihydromorphanthridine.

BACKGROUND OF THE INVENTION In both Parkinsons disease and drug-induced extrapyramidal disorders, the patient exhibits one or more of the following symptoms: tremor, rigidity, increased salivation, akathisia, manifested by extreme restlessness, and dyskinesias, characterized by spastic contractions and involuntary movements.

The drug most widely prescribed for use in the treatment of Parkinsons disease and the drug-induced extrapyramidal disorders is 3-(l-pyridyl)-1-phenylcyclohexyl-1- propanol hydrochloride. Unfortunately, this agent and SUMMARY OF THE INVENTION In the practice of the invention, an animal, especially a person afflicted with Parkinsons disease or a drug-induced extrapyramidal disorder, is administered a safe and effective amount of a compound or a nontoxic salt of a compound selected from compounds of the formulae:

3,497,596 Patented Feb. 24, 1970 in which X and X are selected from hydrogen, a halogen such as chloro or bromo, a lower alkoxy such as methoxy or ethoxy, a lower alkyl thio such as thiomethyl or thioethyl and trifluo'romethyl, R is hydrogen, a lower alkyl of l to 4 carbon atoms or a phenyl-lower alkyl of 7 to 13 carbon atoms such as benzyl, phenethyl, phenylisopropyl, and the like, A is a straight or branched chain lower alkylene of 2 to 6 carbon atoms, and R and R are selected from hydrogen, a lower alkyl of 1 to 4 carbon atoms and phenyl-lower alkyl of 7 to 10 carbon atoms represent groups in which R and R are joined together to form a cyclic group selected from morpholino, pyrrolidino, piperidino, piperazino and 4-lower alkyl piperazino.

DETAILED DESCRIPTION In the preferred practice of the present invention, pharmaceutical compositions containing a major amount of a pharmaceutical diluent and one or more of the described morphanthridine derivatives are administered orally or parenterally to patients afflicted with Parkinsons disease or a drug-induced extrapyramidal disorder in doses ranging from 2 mg. per day to mg. or more a day depending upon the severity of the condition and the response of the patient to the active ingredients.

The pharmaceutical compositions which may be employed are oral dosage forms such as tablets, coated or uncoated, of the immediate or sustained release type, capsules, syrups, elixirs or dosage forms adapted for other routes of administration such as suppositories, and sterile parenteral solutions and the like.

The active ingredients may be incorporated into the pharmaceutical compositions as the free bases; however, it is usually preferred to employ them in the form of a pharmaceutically acceptable salt. Representative of the acid addition salts which, may be employed are the hydrochloride, sulfate, phosphate, acetate, fumarate succinate, maleate, sulfamate, and dicyclohexylsulfamate.

Among the compounds of Formula I which may be employed in the method of the invention are the followmg:

5 -methyl-1 l- 3-dimethylamino propylidene-S ,6-

dihydromorphanthridine,

5 -methyl-1 1- 3-dirnethylamino-2-methylpropylidene 5,6-dihydromorphanthridine,

S-methyl-l 1- 3-methylamino propylidene-5,6-

dihydromorphanthridine,

3-chloro-5-methyl-l 1- 3-dimethylamino propylidene- 5,6-dihydromorphanthridine, and

5 -rnethy1-1 1- 3- (4-methylpiperazino -propylidene] -5,6-

dihydromorphanthridine.

Each of the above compounds, when administered to mice in doses of 20 mg./kg. intraperitoneally, prior to challenge with either tremorine or oxotremorine, blocked the tremors normally induced when tremorine or x0- tremorine are administered to nonpretreated mice intraperitoneally. This is considered a significant indication of anti-Parkinsonism activity, for both tremorine and 0x0- tremorine induce a Parkinson disease-like behavior characterized by tremor, rigidity and parasympathomimetic stimulation in mice, rats, rabbits, dogs and monkeys. The similarity of tremorine and oxotremorine-induced behavior in animals to that seen in Parkinsons disease in man, and the fact that all agents found to be useful in treating Parkinsons disease also block the etfects of tremorine and oxotremorine in animals, has led to the general use of tremorine and oxotremorine in the screening of drugs for anti-Parkinsonism activity (Everett, et al., Science, 124, 79 (1956) and Cho, et a1. Biochem. biophys. Res. Communs. 5, 276 (1961)).

Compounds of Formula II which may be employed in the method of the invention are the following:

S-benzyl-l 1-[4-(N-methyl-4-piperidylene) ]-5,6-

dihydromorphanthridine, and

S-methyl-l l-(N-methyl-4-piperidylene) -5,6-

dihydromorphanthridine.

Each of the above compounds blocked tremorine-inluced tremors when administered to mice prior to chalenge in doses of less than 10 mg./kg. intraperitoneally.

Compounds of Formula III which may be employed in he method of the invention are the following:

i-methyl-l1-(3-piperidino)propyl-5,6-

dihydromorphanthridine,

i-methyl-l l- 3- (N'-methyl piperazine] propyl-5,6-

dihydromorphanthridine,

i-methyl-l 1-( 3 -methylamino propyl-S, 6-

dihydromorphanthridine,

i-methyl-11-(1-dimethylamino-3-butyl)-5,6-

dihydromorphanthridine,

l-chloro-S -methyl-1 1- 3-N-methyl-N-benzylamino) propyl-5,6-dihydromorphanthridine, and

I-chloro-S -methyl-1 1- 3-methylamino propyl-5,6-

dihydromorphanthridine.

Each of the above compounds blocked tremorine-inluced tremors when administered to mice prior to chalenge in doses of less than 20 mg./kg. intraperitoneally.

Representative of suitable pharmaceutical composiions which may be prepared are the following:

TABLETS -methyl-l 1- 3 -dimcthylamino propylidene-5,6-dihydromorphanthridine dicyclohexylsulfamate 25 /Iethyl cellulose, 400 cps. 4 .actose 9 llagnesium stearate 0.4 tarch 1.6

The powders, other than magnesium stearate, are granilated with water, passed through a No. 16 mesh screen .nd dried at 50 C. Magnesium stearate is mixed in and -0 mg. tablets are pressed.

The practice of the invention is further illustrated by be following example:

EXAMPLE Sixteen human patients suifering from Parkinsons disase were administered tablets containing 2 mg. each of he compound -methyl-l1-(3-dimethylamino)propyliene-5,6-dihydromorphanthridine. The following is a ummary of the results of the study. The patients received oses ranging from '6 mg. per day to 50 mg. per day. All ixteen of the pat ents had tremor. Eleven of the patients responded favorably to the medication with reduced tremor. Of the eight patients that had rigidity, in addition to tremor, six improved on the medication. As part of the controlled study, placebos were administered in six cases, however, no placebo response was observed.

The method of the present invention appears to possess a significant advantage over previous treatments of Parkinsons disease in that the beneficial effects of the method are not accompanied by the same degree of undesirable peripheral anticholinergic activity as previous methods.

I claim:

1. A method of controlling the tremor and rigidity of Parkinsons disease or a drug-induced extra-pyramidal disorder in an animal which is afiiicted with said disease or disorder which comprises administering to said animal a daily dose of 2 to mg. of a compound of the formulae:

X X1, X X

I II

III

in which X and X are hydrogen, halogen, lower alkoxy, lower alkyl thio or trifluoromethyl, R is hydrogen, lower alkyl of 1 to 4 carbon atoms or a phenyl-lower alkyl of 7 to 10 carbon atoms, A is an alkylene of 2 to 6 carbon atoms, R and R are hydrogen, lower alkyl of 1 to 4 carbon atoms, a phenyl-lower alkyl of 7 to 10 carbon atoms and when taken with the attached N are morpholino, pyrrolidino, piperidino, piperazino or 4-lower alkyl piperazino.

2. The method of claim 1 in which the compound administered is a compound of Formula 1 in which R is methyl, A is ethylene, X and X are hydrogen and R and R are methyl.

3. The method of claim 1 in which the compound administered is one in which X and X are hydrogen or chloro.

4. The method of claim 1 in which the animal is a human being.

References Cited UNITED STATES PATENTS 3,153,652 10/1964 Drukker et a1. 424-267 3,267,094 8/1966 Drukker et a1.

OTHER REFERENCES Current Therapy, Conn. (1966), pp. 603-608.

ALBERT T. MEYERS, Primary Examiner S. J. FRIEDMAN, Assistant Examiner UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,497,596

- February 24, 1970 Richard Ursillo It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

Column 4, lines 25 to 30,

that portion of the formula reading I should read Signed and sealed this 15th day of September 1970.

( Attcst:

Edward M. Fletcher, Jr. Attcsting Officer WILLIAM E. SCHUYLER, JR.

Commissioner of Patents 

